There is a consistent need for ready blood products for an ever-increasing surgical and trauma load, and to supplement blood bank shortages. Oxygen carrying solutions, such as hemoglobin-derived solutions can be used in place of whole blood or red blood cells for patients having a need for augmented oxygen carrying capacity. Because they are not dependent upon donor availability, such solutions can be made readily available in an emergency situation or during a blood bank shortage. Also, due to risk of infection of blood borne pathogens as a result of a blood transfusion, a patient may prefer a hemoglobin-derived solution for transfusion in place of whole blood or red blood cells. In particular, such solutions may include, but are not limited to, oxygen carriers, blood substitutes, and hemoglobin-derived compositions such as those disclosed in U.S. Pat. Nos. 6,133,425, 5,464,814, 5,438,041, 5,217,648, 5,194,590, 5,061,688, and 4,826,811, the teachings of which are incorporated herein by reference in their entirety.
Active hemoglobin is an oxygen (O2) transporting protein found in red blood cells. Each hemoglobin molecule is comprised of four protein chains and four porphyrin molecules known as heme. In the middle of each heme is an iron atom that is partially oxidized to the (+2) state. When oxygen is transported under normal conditions in vivo, oxygen is bound to the heme without a change in valence of the iron ion; the hemoglobin thus becomes oxyhemoglobin. To indicate that this binding occurs without a change in valence, the reaction is called oxygenation (rather than oxidation), and the reverse process is deoxygenation. Hemoglobin is called deoxyhemoglobin to emphasize its oxygen free state.
Apart from oxygenation of the heme group, further oxidation of the iron atom can occur; the result is conversion of the bivalent iron ion to the trivalent state (+3). Hemoglobin having an oxidized heme group is known as methemoglobin. Human blood normally contains only a very small percentage of methemoglobin, but the amount can be increased by certain toxins and in some diseases. Such a condition is dangerous because methemoglobin does not transport O2 to the body tissues.
Because methemoglobin does not transport O2, the presence of methemoglobin in a hemoglobin solution should be avoided. Accordingly, the storage and handling of hemoglobin solutions is a critical part of their effectiveness. Storage requirements include the need to maintain the hemoglobin solutions in an essentially oxygen free environment in order to prevent the oxidation of hemoglobin to methemoglobin.
A common storage container for a medical solution, such as a hemoglobin solution, is a flexible container made of plastic polymer film, most notably an I.V. bag. Unlike I.V. bags for many other solutions, I.V. bags used specifically for hemoglobin solutions stored in a deoxygenated state must also provide a sufficient barrier to the passage of moisture vapor and other gasses to preserve the deoxygenated state of the hemoglobin solution contained therein. Further, the container for a hemoglobin solution should be made from a material that complies with U.S. Pharmacopeia (USP) Class VI classification (physical, chemical and biocompatibility) and that is non-pyrogenic.
In addition, these bags must meet a number of performance criteria, including collapsibility, optical clarity and transparency, and mechanical strength. Collapsibility is necessary in order to ensure proper and complete delivery or drainage of the bag. In order for the bag to be collapsible, the film from which the bag is made must be flexible. Thus, a key consideration in the design of films used to produce medical solution bags is that the film must have sufficient flexibility that the resultant medical bag is collapsible enough to be fully drainable. The container must be optically clear so that, prior to administering a medical solution from a bag and into a patient, a visual inspection of the solution contained within the container may be performed to determine whether the solution has deteriorated or has been contaminated. Therefore, it is essential that the container meet a level of optical properties, i.e., a high degree of clarity and transmission of light.
Typically, hemoglobin solutions cannot be terminally heat sterilized due to the degradation of the hemoglobin molecule and therefore must be aseptically filled. Thus, for purposes of sterilization, the containers must be, for example, gamma irradiated or washed in a hydrogen peroxide bath or exposed to an ethylene oxide environment. Therefore, another requirement of medical solution containers is that they must be able to endure the high dosages of gamma irradiation without discoloration or deterioration due to material degradation via polymer chain scissioning.
Finally, medical solution containers must also have sufficient mechanical strength to withstand the abuse which is typically encountered in the administration and handling of the solution. For example, in some circumstances, a plastic or rubber bladder is placed around a medical solution-containing bag and pressurized to, for example, approximately 300 mm Hg, in order to force the solution out of the pouch and into a patient. Such a bladder is commonly referred to as a “pressure-cuff” and is used, for example, when a patient is bleeding profusely in order to quickly replace lost fluids and restore oxygen carrying capacity or, for example, when resistance in the intravenous fluid path is high (e.g., long lines, small catheter, etc.) such that a greater opposing pressure must be generated in the bag in order to introduce in a timely fashion the medical solution into the patient.